- Title
- Methyl donor supplementation reduces phospho-Tau, Fyn and demethylated protein phosphatase 2A levels and mitigates learning and motor deficits in a mouse model of tauopathy
- Creator
- van Hummel, Annika; Taleski, Goce; Sontag, Jean-Marie; Feiten, Astrid Feentje; Ke, Yazi D.; Ittner, Lars M.; Sontag, Estelle
- Relation
- Neuropathology and Applied Neurobiology Vol. 49, Issue 4, no. e12931
- Publisher Link
- http://dx.doi.org/10.1111/nan.12931
- Publisher
- Wiley-Blackwell
- Resource Type
- journal article
- Date
- 2023
- Description
- Background: Reduced folate status and elevated levels of circulating homocysteine are modifiable risk factors for cognitive decline and dementia. Disturbances in one-carbon metabolism are associated with the pathological accumulation of phosphorylated tau, a hallmark feature of prevalent dementia, including Alzheimer's disease and subgroups of frontotemporal dementia. Methods: Here, using transgenic TAU58/2 mouse models of human tauopathy, we tested whether dietary supplementation with L-methylfolate (the active folate form), choline and betaine can reduce tau phosphorylation and associated behavioural phenotypes. Results: TAU58/2 mice fed with the methyl donor-enriched diet showed reduced phosphorylation of tau at the pathological S202 (CP13) and S396/S404 (PHF-1) epitopes and alleviation of associated motor and learning deficits. Compared with mice on the control diet, the decrease in cortical phosphorylated tau levels in mice fed with the methyl donor-enriched diet was associated with enhanced methylation of protein phosphatase 2A, the major brain tau Ser/Thr phosphatase. It also correlated with a reduction in protein levels of Fyn, a tau tyrosine kinase that plays a central role in mediating pathological tau-induced neurodegeneration. Conversely, Fyn expression levels were increased in mice with deficiencies in folate metabolism. Conclusions: Our findings provide the first experimental evidence that boosting one-carbon metabolism with L-methylfolate, choline and betaine can mitigate key pathological, learning and motor deficits in a tauopathy mouse model. They give support to using a combination of methyl donors as a preventive or disease-modifying strategy for tauopathies.
- Subject
- Alzheimer's disease; folate; Fyn; methylation; one-carbon metabolism; PP2A
- Identifier
- http://hdl.handle.net/1959.13/1488773
- Identifier
- uon:52534
- Identifier
- ISSN:0305-1846
- Language
- eng
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